The long-term objectives are to elucidate the molecular mechanisms involved in muscle wasting associated with various pathophysiological conditions. Skeletal muscle catabolism, a characteristic metabolic response to fever, sepsis, severe injury, or cancer, is mainly caused by accelerated protein breakdown (in particular degradation of myofibrillar protein) and reduced protein synthesis. The mechanisms and regulators of this response in skeletal muscle are not clear. Previous studies have implicated glucocorticoids and cytokines, such as tumor necrosis factor and interleukin-1 released from activated macrophages and lymphocytes, as the mediating factors. However, the role of cytokines and their interaction with glucocorticoids in inducing skeletal muscle catabolism is poorly understood. Since severe loss of body protein may limit the ability of injured patients to recover, elucidation of the mechanisms responsible for this excessive protein breakdown is of appreciable importance for medicine and surgery. To elucidate, using rats as a model system, glucocorticoid- cytokine interaction in the regulation of protein turnover in skeletal muscles of different fiber composition, this project has the following specific aims: a) To evaluate acute and chronic effects of tumor necrosis factor (TNF) and interleukin-1 (IL-1) on protein synthesis and total and myofibrillar protein breakdown in slow-twitch soleus and fast-twitch extensor digitorum longus (EDL), and b) To investigate the role of glucocorticoids in TNF and IL-1 induced alterations in protein synthesis and total and myofibrillar protein breakdown in soleus and EDL. Protein synthesis will be measured as incorporation of 3H-tyrosine into muscle protein. Total and myofibrillar protein breakdown rates will be assessed as release of tyrosine and 3-methylhistidine, respectively. Future work will be focused on further elucidation of mechanisms involved in protein catabolism during sepsis, etc., in a muscle derived cell line (L-6 myotubes).